Prostaglandin D2 (PGD2) is an eicosanoid generated by the metabolism of arachidonic acids upon stimulation of inflammatory cells with allergens, inflammatory stimuli or by tissue damage. PGD2 is primarily released by mast cells with Th2 cells, dendritic cells, and macrophages being secondary sources. PGD2 is the major arachidonic acid metabolite produced by mast cells upon allergen challenge (Lewis et al., J. Immunol. 1982, 129:1627-1631) and has been detected in high concentrations in the airways of asthmatic patients (Murray et al., N. Engl. J. Med., 1986, 315:800-804; Liu et al., Am. Rev. Respir. Dis., 1990, 142 126-132; Zehr et al., Chest, 1989, 95:1059-63; Wenzel et al., J. Allergy. Clin. Immunol., 1991, 87540-548). PGD2 production is also increased in patients with systemic mastocytosis (Roberts N. Engl. J. Med. 1980, 303, 1400-1404; Butterfield et al., Int Arch Allergy Immunol, 2008, 147:338-343) allergic rhinitis (Naclerio et al., Am. Rev. Respir. Dis., 1983, 128:597-602; Brown et al., Arch Otolaryngol Head Neck Surg, 1987, 113:179-183; Lebel et al., J. Allergy Clin. Immunol., 1988, 82:869-877), urticaria (Heavy et al., J. Allergy. Clin. Immunol., 1986, 78:458-461), chronic rhinosinusitis (Yoshimura et al., Allergol. Int., 2008, 57:429-436), chronic obstructive pulmonary disease (Csanky et al., Electrophoresis, 2009, 30:1228-1234) and during anaphylaxis (Ono et al., Clin. Exp. Allergy, 2009, 39:72-80).
Instillation of PGD2 into airways can provoke features of asthmatic response including bronchoconstriction (Hardy et al., 1984, N Engl J. Med 311:209-213; Sampson et al. 1997, Thorax 52: 513-518) and eosinophil accumulation (Emery et al., 1989, J. Applied Physiol 67: 959-962). The potential of PGD2 to trigger inflammatory responses has been confirmed by the overexpression of human PGD2 synthase in mice resulting in elevated eosinophil lung inflammation and Th2 cytokine production in response to allergen (Fujitani et al., 2002 J. Immunol. 168:443-449).
PGD2 is an agonist of two 7-transmembrane type G protein-coupled receptors, the PGD2 receptor DP1 (Boie et al., J Biol Chem, 1995, 270:18910-6) and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as DP2 receptor) (Nagata et al., J. Immunol., 1999, 162:1278-86).
CRTH2 is expressed on Th2 cells, eosinophils, basophils and mast cells (Nagata et al., FEBS Lett, 1999, 459: 195-199; Nagata et al., J Immunol, 1999, 162: 1278-1286; Cosmi et al., Eur J Immunol, 2000, 30:2972-2979; Boehme et al., Int Immunol, 2009, 21: 621-32). Using selective CRTH2 agonists like 13,14 dihydro-15-keto-PGD2 (DK-PGD2) and 15R-methyl-PGD2, it has been shown that CRTH2 activation initiates cellular processes that lead to the recruitment and activation of inflammatory cells (Spik et al., J. Immunol., 2005; 174:3703-8; Shiraishi, J. Pharmacol. Exp. Ther., 2005, 312:954-60; Monneret et al., J. Pharmacol. Exp. Ther., 2003, 304:349-355). Using CRTH2 selective antagonists it has been shown that inflammatory responses and pathophysiological changes in animal models of diseases like asthma, allergic rhinitis, atopic dermatitis and COPD can be diminished (Uller et al., Respir Res. 2007, 8:16; Lukacs et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2008, 295:L767-79; Stearns, Bioorg. Med. Chem. Lett. 2009, 19:4647-51; Nomiya, J Immunol, 2008, 180:5680-5688; Boehme et al., Int. Immunol., 2009, 21:1-17; Boehme et al., Int Immunol, 2009, 21:81-93; Takeshita et al., Int Immunol, 2004, 16:947-59; Stebbins et al., J. Pharmacol. Exp. Ther. 2009). Moreover, genetic deletion of CRTH2 in mice diminished inflammatory responses in animal models of allergy (Shiraishi et al., J. Immunol. 2008; 180:541-549; Oiwa, Clin Exp Allergy, 2008, 38:1357-66; Satoh et al., J. Immunol., 2006, 177:2621-9). In contrast, the selective DP1 agonist BW245C does not promote inflammatory responses, like migration or activation of Th2 lymphocytes, basophils or eosinophils (Yoshimura-Uchiyama et al., Clin. Exp. Allergy, 2004, 34:1283-90; Xue et al., Immunol, 2005, 175:6531-6; Gervais et al., J. Allergy Clin. Immunol., 2001, 108:982-8). Therefore, agents that antagonize the effects of PGD2 at the CRTH2 receptor should be useful for the treatment of respiratory or gastrointestinal complaints, as well as inflammatory diseases of the joints and allergic diseases of the nasopharynx, eyes and skin.
WO 2004/096777 teaches pyrimidine derivatives of formula (a) and salts thereof,
wherein R6 is carboxy, carboxamide, nitrile or tetrazolyl, the derivatives having CRTH2 antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with CRTH2 activity.
WO 2009/042138 claims alkylthio substituted pyrimidine compounds of formula (b),
the compounds having CRTH2 antagonistic activity.
WO 2009/042139 claims 2-S-benzyl pyrimidine compounds of formula (c),
the compounds having CRTH2 antagonistic activity.
EP 0 480 659 claims compounds of general formula (d),
wherein Z2 inter alia may be carboxyl-C1-C10-alkyl-C═ and Y may be substituted benzyl, the compounds being useful for the treatment of hyperuricemia.
WO 2005/040128 claims compounds of general formula (e),
the compounds being useful for the treatment of conditions such as pain, or an inflammatory, immunological, bone, neurodegenerative or renal disorder.
WO 01/38325 claims compounds of general formula (f),
wherein A is an aromatic ring and B is a nitrogen-containing 5-membered hetero ring which may further be substituted, the compounds having hypoglycemic and hypolipidemic activity.
It is an objective of the present invention to provide further compounds having CRTH2 antagonistic activity.
Preferably the compounds of the present invention have enhanced chemical stability, enhanced pharmacokinetic properties (PK) and/or enhanced activity in a whole cell assay.